The objective of the proposed research is to illuminate the mechanisms by which mechanical stresses influence the differentiation, growth, organization and adaptation of artery walls. It is our intent to utilize two relevant and complementary model systems developed in our laboratory to characterize the metabolic and biosynthetic responses of connective tissue cells to pulsatile mechanical stresses. The first model is an in vitro system in which arterial smooth muscle cells or fibroblasts cultured on elastin membranes are induced to modulate their biosynthetic response by cyclic stretching. The second is an in vivo system in which subcutaneous tissues of living animals are induced to form distinctly layered, sharply delineated fibrocellular sheaths about implanted pulsating tubes. The effects of frequency, amplitude, and the relative durations of the stretching and relaxation phases will be quantitated in both systems. In the tissue culture system, responses will be monitored with respect to cytoarchitecture, to the elaboration of extracellular macromolecules (collagen, elastin, proteoglycosaminoglycans), as well as the intermediate stages in their production and the roles of ionic and hormonal mediators and cyclic nucleotides in their biosynthetic regulation. In the in vivo tissue pulsation system, biosynthetic response will be monitored by means of autoradiography and tissue composition and organization by means of steriology. A related series of experiments utilizing these models is designed to compare the effects of mechanical stress on cholesterol metabolism of smooth muscle cells and fibroblasts. The data should provide new insights into the mechanisms by which mechanical stimuli regulate connective tissue composition and organization and the models should permit us to test hypotheses regarding the nature of the arterial medial response to hypertension, elavated serum lipids and other metabolic states.